Several patents and printed publications are referenced in this application in order to more fully describe the state of the art to which this invention pertains. The disclosure of each of these publications is incorporated by reference herein, in its entirety.
Presently, surgery, radiation therapy, and chemotherapy are the primary treatment modalities for cancer. Over the past several decades, chemotherapy and radiation therapy coupled with surgery have contributed to a significant reduction in cancer mortality. However, the potential utility of chemotherapeutic drugs and radiation therapy in the treatment of cancer have not been fully exploited due to adverse effects associated with the nonspecific cytotoxicity of these agents or treatments. Alkylating agents used alone or in combination with other chemotherapeutic agents, are used in approximately half of all chemotherapy treatments. Alkylating agents interfere with the proliferation of cancerous cells by inhibiting DNA replication. Non-alkylating cancer chemotherapy drugs are also toxic to mammalian cells; they can inhibit multiple sites within a replicating cell, such as (1) synthesis of nucleotides required for DNA replication and (2) microtubule function required for mitosis, to name just two. Radiation therapy, which achieves most of its cell killing properties by generating oxygen radicals within cells, can also efficiently kill mammalian cells. Cell death is then accomplished by lethal DNA mutations that prevent cell function and division.
The foundation for both radiation and chemotherapy is to target and kill rapidly growing cells. Selective killing of only cancer cells while sparing normal functioning cell populations remains the greatest challenge in cancer therapy. The medical literature describes many major side effects from cancer treatments. All are outcomes of the unwanted killing of normal, non-neoplastic cells. These side effects from chemotherapy and/or radiation therapy range from mild to life-threatening. There is a large effort to increase the selectivity of cancer chemotherapies, but currently, very few such compounds exist. As a result, persons being treated with one or more of these cancer therapies commonly develop numerous clinical complications.
The toxicity of cancer therapy for epithelial cells accounts for many of the side effects commonly suffered by persons undergoing a regimen of chemotherapy or radiotherapy. These include gastrointestinal distress, nausea, vomiting, diarrhea, loss of appetite, hair loss, bone marrow suppression and skin rash or ulceration at the site of irradiation. These complications can be so difficult to endure that it is not uncommon for people to forego or discontinue recommended cancer therapy treatments in order to avoid the side effects. Gastrointestinal disturbances may compromise a patient's chances of recovery, because they make it difficult for the patient to obtain the nourishment necessary to optimize his ability to fight disease. It appears that chemo- and radiotherapy-associated death and sloughing of GI lumenal cells results in a release of GI damage-associated molecules into the vasculature. These blood-borne molecules, when detected by sites within the brain, trigger the nausea response that is so common among patients receiving chemotherapy. Present treatments with drugs, such as Ondansetron, serve to suppress these brain centers and thus diminish the nausea response. However, the primary destruction of the GI lining still limits the most effective use of chemotherapy. A better mechanism to diminish nausea in these patients would be to eliminate the primary destruction of the GI surface and thus prevent the release of damage-associated, nausea-inducing molecules, rather than just suppressing the effects of these molecules in the brain. Typically, during the course of chemotherapy, the chemotherapeutic agent is administered in sub-optimal doses in order to minimize toxicity and to protect normal, drug-sensitive cells. Reducing the sensitivity of normal cells to chemotherapeutic agents would allow the administration of higher drug dosages and chemotherapy could be rendered more effective.
An especially insidious side effect from chemotherapy and/or radiation therapy is alopecia. Alopecia or hair loss is the most common hair growth disorder in humans and is often the cause of great concern in affected individuals. In patients with acquired alopecia associated with cancer chemotherapy or radiation therapy, the loss of hair ranked above vomiting as an important concern. A National Cancer Institute (NCI) study has indicated that hair loss during chemotherapy is the most psychologically debilitating aspect of cancer treatment. It is estimated that approximately 60–70% of all patients receiving cancer chemotherapy experience alopecia. Hair loss represents a psychologically distressing effect that can cause negative changes in body image, decreased social activity and altered interpersonal relationships and may lead to refusal of further chemotherapy.
The phenomenon of chemotherapy-induced alopecia is believed to result from cytotoxic and apoptosis-related damage to the hair follicle. The pathobiologic mechanisms that underlie chemotherapy induced follicle damage are characterized by bulging of the dermal papilla, kinking and distension of the follicular canal and disruption of the melanogenic apparatus.
Several approaches have been employed in an attempt to protect patients from chemotherapy-induced alopecia. These have included physical modules that temporarily decrease scalp blood flow and drug contact time with the hair follicle, but the patient tolerance was very poor. These poor results led to the development of scalp cooling methods that decrease both the metabolic rate of follicular stem cells and blood flow to the follicle matrix, but this strategy was found to be unsuccessful. The use of dietary alpha-tocopherol, a free radical scavenger, was shown to have a protective effect in rabbits but not in humans. Minoxidil 2% solution was also found to be ineffective in treating chemotherapy-induced alopecia. Pre-treatment of rodents with growth factors and cytokines provided some degree of protection against alopecia induced by ARA-C (cytosine arabinoside) but not the commonly used cancer drug cytoxan.
Reversal of cyclophosphamide-or cyclophosphamide/cytarabine-induced alopecia by N-acetylcysteine (NAC) or NAC/ImmuVert, administered parenterally or applied topically in liposomes, has been reported in a rat model system (Jimenez et al., Cancer Investigation 10: 271–276, 1992). NAC is a precursor of glutathione and, as such, is believed to function as a detoxifying agent by increasing intracellular GSH levels. This sort of therapy is limited in efficacy, inasmuch as it has been shown that intracellular GSH levels can only roughly double in a cell by adding exogenous NAC. (See Ho & Fahl, 1984, J. Biol. Chem. 259: 11231–11235; Carcinogenesis 5: 143–148, 1984).
Compounds that can preferentially slow the growth of normal cells susceptible to cancer therapy are alternative strategies to prevent chemotherapy-induced alopecia. Anti-proliferative agents such as vitamin D derivatives, or cell-cycle inhibitors such as small molecule CDK-2 inhibitors that inactivate certain proteins involved in cell cycle progression have been tested. Unfortunately, most have met with mixed results. Reports indicate that many of these compounds have performed poorly or were irreproducible in preclinical animal studies, or have failed outright in clinical trials.
U.S. Pat. No. 5,753,263 to Lishko et al. discloses methods and compositions for treating alopecia induced by certain chemotherapeutic agents, which comprise topical application of an effective amount of a p-glycoprotein, or MDR gene encoding such a protein, in a liposome carrier. Successful delivery of these proteins and genes to target cells was not demonstrated. Moreover, even if shown to be effective, this therapy is limited to the particular chemotherapeutic agents that can be exported from a cell via the p-glycoprotein pump. Notably excluded from this list are alkylating chemotherapeutic agents.
Thus, while treatments of the types outlined above may provide some relief from chemotherapy-induced hair loss, their utility is limited. Therefore, there remains a continued search for effective compounds that can safely prevent chemotherapy or radiation-induced alopecia.
Radiation-induced dermatitis is another major side effect of cancer treatment. Radiotherapy used regularly as a primary or adjunct therapy, remains largely a nonspecific treatment approach. However, radiotherapy can equally and indiscriminately kill normal dermal cells as well as underlying cancer cells.
Of the many thousand women in the US who will be diagnosed with breast cancer in 1999, a large percentage will receive radiation therapy. It is estimated that 87% of these women will develop some degree of radiation-induced dermatitis, varying from mild to brisk erythema, moist desquamation or even permanent scarring. It is estimated that the severe forms of dermatitis occur in about 60% of all patients receiving palliative radiotherapy. Radiation-induced dermatitis can impose significant and painful discomfort and interfere with the quality of life. It can lead to serious irritation, bacterial infections and in the worst scenario it can cause the suspension of critical cancer treatment. While there has been much attention to how radiation affects the skin, very little research has been performed on identifying and standardizing clinical intervention. A survey of Radiation Therapy Oncology Group (RTOG) institutions in 1995, revealed that 50% of the RTOG institutions used Aloe Vera gel as the treatment of choice. Unfortunately, a study completed in 1991 by the North Central Cancer Treatment Group (NCCTG), reported that Aloe Vera gel did not protect against radiation-induced dermatitis when used prophylatically in women undergoing breast cancer therapy. Alternative compounds used in the survey included Aquaphor (Biersdorf, Lindenhurst, N.Y.), Carasyn Gel or lanolin.
Some of the newer compounds developed to treat radiation-induced dermatitis function either as better moisturizers or are designed to prevent inflammation in the skin. Moisturizers currently being tested, either singly or in combination are Acemannan, a wound dressing gel, Biafine, and Lipiderm. A recent randomized trial indicated that neither Biafine nor Lipiderm seem to have a radio-protective effect. Mixed results have been seen using anti-inflammatory compounds such as a topical cortisone or corticosterioid (mometasone furoate) cream. Interferon gamma treatments have been shown to reduce a severe form of radiation dermatitis, cutaneous radiation fibrosis. Unfortunately, most of these classes of compounds were found to be not very effective when tested in clinical trials.
Sulfhydryl containing aminothiol compounds have shown some promise as therapies to protect against radiation induced-mutations and carcinogenesis. DNA damage by radiation is due largely to the action of free radicals. It is thought that these aminothiol-radioprotectors can serve as free-radical scavengers to reduce this critical damage. In 1959, the U.S. Army initiated an Antiradiation Drug Development Program in which over 4000 compounds were synthesized and tested for their radio-protective abilities. The best radio-protectors contained cysteine, and one compound, S-2-(3-aminopropylamino) ethylphoshorothioic acid, also called WR-2721 or amifostine, provided the best protection thus far. Several studies have shown that this compound administered systemically shows a protective effect against the side effects of radiotherapy. U.S. Pat. Nos. 5,217,964, 5,354,782, 5,434,135 and 6,114,394 also disclose polyamine derivatives asserted to have a radioprotective effect when systemically administered to a subject. The need for systemic administration of these compounds is a significant disadvantage, inasmuch as they could consequently exert a protective effect on the tumor cells themselves, or otherwise have a detrimental effect on non-target organs and tissues, as has been observed in certain clinical trials of systemically administered polyamines that were halted because of very significant host organ toxicity, including severe constipation and neurological toxicity. Adverse reactions, including gastrointestinal and neurological toxicity, during systemic, e.g., intravenous regimens of DENSPM (BE333) also have been noted (Creaven et al. 1997, Invest. New Drugs 15: 227–234; Streiff et al. 2001, Invest. New Drugs 19: 29–39, 2001; Hahm et al. 2002, Clin. Cancer Res. 8: 684–690).
Mucositis is an important and costly side effect of cancer therapy. Mucositis, or inflammation of the mucosal lining, is frequent and a potentially severe complication from chemotherapy and/or radiotherapy. It can manifest as erythema, desquamation, ulcer formation, bleeding and exudate. It is generally accepted that mucositis results from the direct inhibitory effects of chemotherapy or radiotherapy on DNA replication and mucosal cell proliferation. These events result in the reduction in the regeneration capability of the basal epithelium leading to mucosal atrophy, collagen breakdown and ulceration. A secondary effect is infection from a number of pathogens after the breakdown of the protective mucosal barrier.
Mucositis can be present anywhere throughout the gastrointestinal and urogenital tract, from the oral cavity to the intestines and rectum. It is particularly debilitating because it can lead to abnormal nutrition, increased systemic infections, use of narcotics to diminish pain, and postponement of cancer therapy. Patient-related risk factors for mucositis include, hematological malignancies and poor oral health. Therapy-related risk factors include, the chemotherapy used (e.g., antimetabolites), dose of drug or radiation, and concomitant therapy. Oral mucositis is a complication in 40% of patients receiving chemotherapy, and in 75% of those exposed to high dose chemotherapy with bone marrow transplantation. The prevalence of gastrointestinal mucositis has been reported to range from 30–39%, although prevalence from 40% to 75% has been reported for antimetabolites such as 5-fluorouracil. In addition, more than 90% of patients irradiated for head and neck cancer experience oral mucositis. Consequently, complications relating to mucositis from chemotherapy and/or radiotherapy lead to increased morbidity, the need for parenteral nutrition, and increased costs of hospitalization.
Presently, no commercial drugs are believed to be available specifically designed to prevent mucositis due to cancer therapy. Only simple preventative measures now exist for oral mucositis involving basic principles of oral hygiene and therapies such as topical anesthetics and systemic analgesics to relieve pain. Auxiliary preventative measures to protect normal cells of the GI tract involve nutrient stimulation and maximizing the intake of growth factors. However, those therapies are primarily superficial approaches which do not address the cause of mucositis. Therefore, there is a real need for safe and effective drugs that can effectively reduce mucositis from cancer therapy.
Approaches into the prevention of mucositis induced by cancer therapy can be divided into three broad categories: One approach promotes mucosal alterations using mucosally active modifiers to reduce delivery and secretion of the chemotherapeutic agent to mucosal cells; the second focuses to increase or modify the proliferative capabilities of the mucosa, and the third aims to reduce the potential for infections and inflammation. The value of using delivery and secretion modifiers such as propantheline or pilocarpine, that can either decrease or increase salivation, respectively, is presently being evaluated. Investigators have studied various agents that modify epithelial proliferation. These include certain cytokines, (granulocyte colony-stimulating factor, (G-CSF); granulocyte-macrophage colony-stimulating factor, (GM-CSF)), beta-carotene, and glutamine. However, these compounds have either failed to show benefits in placebo-controlled clinical trials (e.g., glutamine) or the clinical data is lacking (e.g., G-CSF, GM-CSF). Studies using the anti-microbial/anti-inflammatory approach have shown some benefit in oral mucositis after radiation. Lozenges containing polymyxin B, tobramycin, and amphotericin B prevented oral infections. This approach, while a useful supplementary therapy, fails to treat the direct causes of mucositis. Overall, while some agents have been identified that may be able to accelerate healing and alter the progression of mucositis, currently no intervention exists that is successful at preventing mucositis.
It is clear from the foregoing discussion that there exists a significant unmet medical need to identify novel agents that can prevent and/or treat the side effects of cancer therapies. The successful implementation of protective therapies that promote routine growth and proliferation of normal cells in the presence of radiotherapy or chemotherapeutic agents will permit the use of higher dose, more aggressive chemotherapy. Consequently, these protective therapies may not only address the side effects of cancer but may enable greater efficacy against cancer than that seen using current therapies. Two important targets for development of such protective therapies are (1) the epithelial cells lining the oral and entire gastrointestinal (GI) or urogenital tract, and (2) the epithelial cells of the skin, including hair follicles and the epidermis. While certain treatments of the types outlined above may provide some relief from chemotherapy or radiotherapy-induced side effects, their effectiveness and utility is limited, underscoring the requirement for new effective therapies.